5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors

A series
of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting
the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding
site on HIV-1 integrase, an attractive target for antiviral chemotherapy,
was prepared and screened for activity against HIV-1 infection in
cell culture. Small molecules that bind within the LEDGF/p75-binding
site promote aberrant multimerization of the integrase enzyme and
are of significant interest as HIV-1-replication inhibitors. Structure–activity-relationship
studies and rat pharmacokinetic studies of lead compounds are presented.